The induction of SHP-1 degradation by TAOK3 ensures the responsiveness of T cells to TCR stimulation.

Autor:	Poirier A; Goodman Cancer Institute, McGill University, Montréal, H3A 1A3 Québec, Canada.; Faculty of Medicine and Health Sciences, Division of Experimental Medicine, McGill University, Montréal, Québec, Canada., Ormonde JVS; Brazilian Biosciences National Laboratory, Center for Research in Energy and Materials (LNBio - CNPEM), Campinas, São Paulo, Brazil., Aubry I; Goodman Cancer Institute, McGill University, Montréal, H3A 1A3 Québec, Canada.; Department of Biochemistry, McGill University, Montréal, Québec, Canada., Abidin BM; Goodman Cancer Institute, McGill University, Montréal, H3A 1A3 Québec, Canada., Feng CH; Goodman Cancer Institute, McGill University, Montréal, H3A 1A3 Québec, Canada.; Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada., Martinez-Cordova Z; Goodman Cancer Institute, McGill University, Montréal, H3A 1A3 Québec, Canada.; Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada., Hincapie AM; Goodman Cancer Institute, McGill University, Montréal, H3A 1A3 Québec, Canada.; Department of Biochemistry, McGill University, Montréal, Québec, Canada., Wu C; Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada., Pérez-Quintero LA; Goodman Cancer Institute, McGill University, Montréal, H3A 1A3 Québec, Canada., Wang CL; NYU Langone Medical Center, 660 1st Ave, Fl 5, New York City, NY 10016, USA., Gingras AC; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, Canada., Madrenas J; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 40095, USA., Tremblay ML; Goodman Cancer Institute, McGill University, Montréal, H3A 1A3 Québec, Canada.; Department of Biochemistry, McGill University, Montréal, Québec, Canada.; Faculty of Medicine, McGill University, Montréal, Québec, Canada.
Jazyk:	angličtina
Zdroj:	Science signaling [Sci Signal] 2024 Jan 02; Vol. 17 (817), pp. eadg4422. Date of Electronic Publication: 2024 Jan 02.
DOI:	10.1126/scisignal.adg4422
Abstrakt:	Thousand-and-one-amino acid kinase 3 (TAOK3) is a serine and threonine kinase that belongs to the STE-20 family of kinases. Its absence reduces T cell receptor (TCR) signaling and increases the interaction of the tyrosine phosphatase SHP-1, a major negative regulator of proximal TCR signaling, with the kinase LCK, a component of the core TCR signaling complex. Here, we used mouse models and human cell lines to investigate the mechanism by which TAOK3 limits the interaction of SHP-1 with LCK. The loss of TAOK3 decreased the survival of naïve CD4 + T cells by dampening the transmission of tonic and ligand-dependent TCR signaling. In mouse T cells, Taok3 promoted the secretion of interleukin-2 (IL-2) in response to TCR activation in a manner that depended on Taok3 gene dosage and on Taok3 kinase activity. TCR desensitization in Taok3 -/- T cells was caused by an increased abundance of Shp-1, and pharmacological inhibition of Shp-1 rescued the activation potential of these T cells. TAOK3 phosphorylated threonine-394 in the phosphatase domain of SHP-1, which promoted its ubiquitylation and proteasomal degradation. The loss of TAOK3 had no effect on the abundance of SHP-2, which lacks a residue corresponding to SHP-1 threonine-394. Modulation of SHP-1 abundance by TAOK3 thus serves as a rheostat for TCR signaling and determines the activation threshold of T lymphocytes.
Databáze:	MEDLINE
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